BLOOD PRODUCTS ADVISORY COMMITTEE
94th Meeting, April 2, 2009
Issue Summary
Topic III: Current
Considerations on Plasma Obtained from Whole Blood Donors for Further
Manufacturing Use
Introduction:
Background:
Under current FDA regulations,
Source Plasma (a licensed product) and recovered plasma (an unlicensed product)
are used as source material to manufacture injectable plasma derived products.
Source Plasma (21 CFR 640.60) is
an FDA licensed product collected by plasmapheresis for use in both injectable
and non-injectable products. Source
Plasma standards allow collection of plasma twice within a seven day period,
and incorporate measures to protect donor health due to the frequency of
collection. "Infrequent” Source Plasma has been approved for
manufacture and interstate distribution at some licensed blood establishments
as an alternative procedure. Infrequent Source Plasma is derived from donors
who meet whole blood collection standards and is collected no more than once
per month. Like Source Plasma, it must
be frozen immediately. With the availability of portable devices, apheresis procedures
are now commonly performed away from the primary blood collection facility and
processing laboratory. However, because
of the absence of freezing capability at mobile collections, the manufacture of
Source Plasma (or infrequent Source Plasma) away from the primary facility
generally is infeasible.
Under current FDA regulations,
plasma separated from whole blood collections may be labeled as recovered
plasma and used in further manufacture into injectable or non-injectable
products. Fresh Frozen Plasma (FFP) collected by automated blood cell
separation (apheresis) may also be relabeled as recovered plasma. However, this conversion is permitted only
after its one-year expiration period when the product no longer meets the
definition of FFP in the regulations.
Distribution of recovered plasma in interstate commerce without a
license has historically been permitted under “short supply” regulations. [21
CFR 601.22]
With recent growth in the targeted
collection of cellular blood components by apheresis, whole blood collection
establishments have sought changes in FDA regulations that would permit plasma
collected concurrently during the apheresis procedure to be distributed
immediately for further manufacturing.
Such a change would provide flexibility to blood collectors to
manufacture either FFP or plasma for further manufacturing use based on current
need, without concern that excess FFP might need to be held for one year or
else discarded.
The current state of plasma storage/freezing conditions
for recovered plasma varies widely and is specified in the short supply
agreements between collectors and fractionators or other further manufacturers.
FDA does not routinely review short supply agreements. It is known that
conditions of freezing, thawing, time in contact with cells and time in the
liquid state bear a relationship to preservation, activation and inactivation
of labile proteins (e.g. yields of Factor VIII). For this reason, we are considering
establishing collection, freezing, and storage parameters for Concurrent Plasma and Component Plasma to ensure
minimum quality suitable for the manufacture of injectable plasma derivatives.
Discussion:
FDA is considering the definition
of two new plasma products intended for use in further manufacturing of
injectable or non-injectable end products.
For purposes of this discussion, we are using the following definitions.
The first product, Concurrent Plasma, may be defined as a plasma product
collected concurrently with a cellular product, either by whole blood
collection or by apheresis. Concurrent Plasma could be labeled immediately at
the time of collection, or by one time relabeling (at any time) of previously
collected Fresh Frozen Plasma (or other plasma intended for use in transfusion)
that has been collected concurrently with a cellular product into a product for
further manufacturing. The labeling of Concurrent Plasma may include information
about the separation, freezing, and storage conditions under which the product
was manufactured.
The second new product under
consideration, Component Plasma, may be
derived from one time relabeling of Fresh Frozen Plasma (or other plasma
intended for use in transfusion) that has been collected by plasmapheresis as a
stand-alone product. Alternatively, Component Plasma may be collected directly from
a Whole Blood donor as a stand-alone plasmapheresis product intended for
further manufacture. Whole Blood donors are typically recruited to donate on
behalf of their local community, with the perception that their blood will be
transfused to help save patient lives.
FDA is considering restrictions on the collection of Component Plasma,
both to preserve the health of the donor, and to ensure the continued
availability of donors of whole blood and blood components for
transfusion. Similar to the donation
interval for Infrequent Source Plasma, FDA is considering that Component Plasma
collection may occur no more frequently than one donation per month. The
standards and labeling for Component Plasma could otherwise be similar to those
proposed for Concurrent Plasma.
Standards for
collection, freezing, and storage
Factors involved in the definition
of the new plasma products might include specified limits for collection,
freezing and storage, as well as labeling that would enable the fractionators to identify the conditions under
which the plasma was manufactured.
Since
Concurrent and Component Plasma might both be collected from eligible donors
meeting whole blood donor standards, the primary consideration for additional
standards lies in the conditions of collection, freezing, and storage that
would be reflected in product labeling.
At the Advisory Committee meeting, FDA will summarize information about
processing conditions that affect the quality and safety of plasma. We will
also review information obtained at the 2004 FDA
sponsored workshop on plasma quality
and industry practices regarding the freezing, storage and
shipping of plasma. We will also discuss
US and European regulatory requirements for plasma used for further
manufacturing.
Briefly, conditions that affect plasma quality include: time and temperature of separation of plasma from cells; freezing; storage conditions; thawing conditions; and post thawing environment. Certain proteins such as immunoglobulins and albumin are less affected by these conditions than other more labile proteins such as Factor VIII. For example, Factor VIII is optimally preserved in plasma up to 6-8 hours after donation, but loses about 15% of its activity when stored 16 – 24 hours before freezing. Similarly Factor VIII recovery is improved if freezing is rapid, to a core temperature of -25 C within 12 hr. Adverse collection and storage conditions can promote general proteolytic activity and activate certain enzymes such as Factor XI and XII. Enzyme activation can lead to protein fragmentation and release of small peptides, such as kinins, that can affect product quality, yield, and potentially safety. In light of these observations, FDA is considering specifying manufacturing conditions for Concurrent and Component Plasma that that will help to assure the manufacture of safe and effective plasma products. These candidate specifications are generally consistent with current manufacturing practices.
FDA currently is considering standardized
categories for labeling of Concurrent Plasma and Component Plasma for key
conditions of storage and freezing, so that purchasers in the
|
Concurrent/ Component Plasma Category |
Examples of injectable product |
Separation |
Freeze |
Store |
Shipping |
|
A |
FVIII,
vWF IGIV,
Albumin |
<1 h |
Freezer
at < -20 ◦C |
< -20 ◦C |
< -20 ◦C |
|
B |
FVIII,
vWF IGIV,
Albumin |
<24 h |
Freezer
at < -20 ◦C |
< -20 ◦C |
< -20 ◦C |
|
C |
FVIII, vWF IGIV, Albumin |
<24 h |
Frozen
to a core temperature of < -25 ◦C in <
12 h |
< -20 ◦C |
< -20 ◦C |
|
D |
IGIV,
Albumin |
<72 h |
Freezer
at < -20◦C |
< -20 ◦C |
< -20 ◦C |
|
E |
IGIV,
Albumin |
<120 h |
Freezer
at < -20 ◦C |
< -20 ◦C |
< -20 ◦C |
|
·
Shipping
and storage can exceed -20 °C
for < 72 h total, never > -5 °C (never re-frozen) ·
The product shelf life (in the frozen state) for both
products will be 10 years from date of collection.
·
Labeling will
include an intended use statement: “Caution: For Manufacturing Use Only; Can
be Used to Make Injectable or Non-injectable End Products |
|||||
Regulatory Pathway
Creating definitions of Concurrent
and Component Plasma likely would involve changes to current regulations and
considerations for potential licensure of the new products.
The public health benefit of
defining Concurrent and Component Plasma would be to establish standards for
the collection, storage and freezing for plasma intended for further
manufacturing into injectable end products.
The main benefit from rapid
conversion of Fresh Frozen Plasma for blood establishments lies in reduction of
plasma storage volumes, allowing blood establishment to gain flexibility in the
management of their inventory. However,
since relabeling of Fresh Frozen Plasma under the proposed paradigm would be
uni-directional, blood establishments will need to carefully monitor FFP
supplies to ensure adequate availability of plasma for transfusion. Defining Concurrent and Component Plasma in
the regulations could also facilitate the collection of more male AB plasma
which could facilitate current efforts to reduce the incidence of TRALI.
Should FDA determine that
Concurrent Plasma or Component Plasma products require licensure,
registered-only facilities would need to obtain a biologics license to continue
interstate distribution of plasma products for further manufacture into
injectable products. FDA currently considers that recovered plasma could
continue to be distributed to make non-injectable products under short supply
agreements.
Q2. Please comment on the impact that the proposed new products would have on maintaining the voluntary donor pool that is critical to community-based voluntary blood donation.